Advanced Drug Delivery Reviews 57 (2005) 1556 1568

www.elsevier.com/locate/addr

The basics and underlying mechanisms of mucoadhesionB

John D. Smart *
School of Pharmacy and Biomolecular Sciences, University of Brighton, Lewes Road, Brighton BN2 4GJ, UK
Received 30 July 2004; accepted 12 July 2005

Abstract

Mucoadhesion is where two surfaces, one of which is a mucous membrane, adhere to each other. This has been of interest in
the pharmaceutical sciences in order to enhance localised drug delivery, or to deliver ddifficultT molecules (proteins and
oligonucleotides) into the systemic circulation. Mucoadhesive materials are hydrophilic macromolecules containing numerous
hydrogen bond forming groups, the carbomers and chitosans being two well-known examples. The mechanism by which
mucoadhesion takes place has been said to have two stages, the contact (wetting) stage followed by the consolidation stage (the
establishment of the adhesive interactions). The relative importance of each stage will depend on the individual application. For
example, adsorption is a key stage if the dosage form cannot be applied directly to the mucosa of interest, while consolidation is
important if the formulation is exposed to significant dislodging stresses. Adhesive joint failure will inevitably occur as a result
of overhydration of a dosage form, or as a result of epithelia or mucus turnover. New mucoadhesive materials with optimal
adhesive properties are now being developed, and these should enhance the potential applications of this technology.
D 2005 Elsevier B.V. All rights reserved.

Keywords: Mucoadhesion; Mucoadhesives; Bioadhesion; Bioadhesives; Mucosal delivery; Carbomers

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557
2. Mucous membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557
3. Mucoadhesives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557
3.1. Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557
3.2. Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1558
4. The mucoadhesive/mucosa interaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559
4.1. Chemical bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559
4.2. Theories of adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559

B
This review is part of the Advanced Drug Delivery Reviews theme issue on Mucoadhesive Polymers: Strategies, Achievements and Future
Challenges, Vol. 57/11, 2005.
* Tel./fax: +44 1273 642091.
E-mail address: john.smart@brighton.ac.uk.

0169-409X/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2005.07.001
 J.D. Smart / Advanced Drug Delivery Reviews 57 (2005) 15561568 1557

4.3. Mucoadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1560

4.3.1. The contact stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1560
4.3.2. The consolidation stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1562
5. Removal mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1564
6. Some factors affecting mucoadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1564
7. Liquid and semisolid adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565
7.1. Water soluble polymer adsorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565
7.2. Retention of liquids and gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565
8. New materials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565
9. Conclusions and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1566
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1566

1. Introduction consist of a connective tissue layer (the lamina

propria) above which is an epithelial layer, the sur-
Bioadhesion may be defined as the state in which face of which is made moist usually by the pre-
two materials, at least one of which is biological in sence of a mucus layer. The epithelia may be either
nature, are held together for extended periods of time single layered (e.g. the stomach, small and large
by interfacial forces. In the pharmaceutical sciences, intestine and bronchi) or multilayered/stratified
when the adhesive attachment is to mucus or a (e.g. in the oesophagus, vagina and cornea). The
mucous membrane, the phenomenon is referred to as former contain goblet cells which secrete mucus
mucoadhesion [1]. directly onto the epithelial surfaces, the latter con-
Over the last two decades mucoadhesion has tain, or are adjacent to tissues containing, specia-
become of interest for its potential to optimise loca- lised glands such as salivary glands that secrete
lised drug delivery, by retaining a dosage form at the mucus onto the epithelial surface. Mucus is present
site of action (e.g. within the gastrointestinal tract) or as either a gel layer adherent to the mucosal surface
systemic delivery, by retaining a formulation in inti- or as a luminal soluble or suspended form. The
mate contact with the absorption site (e.g. the nasal major components of all mucus gels are mucin
cavity). The need to deliver dchallengingT molecules glycoproteins, lipids, inorganic salts and water, the
such as biopharmaceuticals (proteins and oligonucleo- latter accounting for more than 95% of its weight,
tides) has increased interest in this area. Mucoadhe- making it a highly hydrated system [2]. The mucin
sives materials could also be used as therapeutic glycoproteins are the most important structure-form-
agents in their own right, to coat and protect damaged ing component of the mucus gel, resulting in its
tissues (gastric ulcers or lesions of the oral mucosa) or characteristic gel-like, cohesive and adhesive proper-
to act as lubricating agents (in the oral cavity, eye and ties. The thickness of this mucus layer varies on
vagina). different mucosal surfaces, from 50 to 450 Am in
This review will consider the basic mechanisms by the stomach [3,4], to less than 1 Am in the oral
which mucoadhesives can adhere to a mucous mem- cavity [5]. The major functions of mucus are that of
brane in terms of the nature of the adhering surfaces protection and lubrication (they could be said to act
and the forces that may be generated to secure them as anti-adherents).
together.

3. Mucoadhesives
2. Mucous membranes
3.1. Materials
Mucous membranes (mucosae) are the moist sur-
faces lining the walls of various body cavities such The most widely investigated group of mucoad-
as the gastrointestinal and respiratory tracts. They hesives are hydrophilic macromolecules containing
1558 J.D. Smart / Advanced Drug Delivery Reviews 57 (2005) 15561568

numerous hydrogen bond forming groups [610], the 3.2. Formulations

so-called dfirst generationT mucoadhesives. Their
initial use as mucoadhesives were in denture fixative First generation mucoadhesive polymers present
powders or pastes [7]. The presence of hydroxyl, significant formulation challenges, being hydrophilic,
carboxyl or amine groups on the molecules favours with limited solubility in other solvents while forming
adhesion. They are called dwetT adhesives in that high viscosity, often pH sensitive, aqueous solutions
they are activated by moistening and will adhere at low concentrations. Dry polymers also become
non-specifically to many surfaces [12]. Once acti- adhesive on exposure to moisture, and so readily
vated, they will show stronger adhesion to dry inert cohere, or adhere to manufacturing equipment or
surfaces than those covered with mucus. Unless delivery devices. Mucoadhesives have been formu-
water uptake is restricted, they may overhydrate to lated into tablets, patches, or microparticles, typically
form a slippery mucilage. Like typical hydrocolloid with the adhesive polymer forming the matrix into
glues, if the formed adhesive joint is allowed to dry which the drug is dispersed, or the barrier through
then, they can form very strong adhesive bonds. which the drug must diffuse [10,12]. Mucoadhesive
Typical examples are carbomers, chitosan, sodium ointments and pastes consist of powdered bioadhesive
alginate and the cellulose derivatives (Fig. 1). polymers incorporated into a hydrophobic base. Solu-
These were used initially largely as they were avail- tions tend to be viscous due to the nature of the
able doff-the-shelfT with regulatory approval, but in mucoadhesive materials. Other proposed mucoadhe-
the last few years, new enhanced materials have been sive formulations include gels, vaginal rods, pessaries
developed. and suppositories [12].

a) Poly(acrylic acid), R = allyl

sucrose or allyl pentaerythritol
(Carbopols); or divinyl glycol
(polycarbophil)
n

b) Chitosan

c) Sodium alginate

n
d) Cellulose derivatives e.g.
Sodium carboxylmethylcellulose
R1, R4 = CH2OH; R2, R3, R5 = OH;
- +
R6=OCH2CO2 Na
Hydroxypropylmethylcellulose
R1=CH2OCH3; R2=OH,
R3=OCH2CHOHCH3; R4=CH2OH;
n R5,R6=OCH3

Fig. 1. The structure of some common dfirst generationT mucoadhesive polymers.

 J.D. Smart / Advanced Drug Delivery Reviews 57 (2005) 15561568 1559

4. The mucoadhesive/mucosa interaction posed to result in the formation of an electrical double

layer at the interface, with subsequent adhesion due to
4.1. Chemical bonds attractive forces.
The wetting theory is primarily applied to liquid
For adhesion to occur, molecules must bond across systems and considers surface and interfacial ener-
the interface. These bonds can arise in the following gies. It involves the ability of a liquid to spread
way [13]. spontaneously onto a surface as a prerequisite for
the development of adhesion. The affinity of a liquid
(1) Ionic bondswhere two oppositely charged for a surface can be found using techniques such as
ions attract each other via electrostatic interac- contact angle goniometry to measure the contact
tions to form a strong bond (e.g. in a salt angle of the liquid on the surface, with the general
crystal). rule being that the lower the contact angle, the
(2) Covalent bondswhere electrons are shared, in greater the affinity of the liquid to the solid. The
pairs, between the bonded atoms in order to spreading coefficient (S AB) can be calculated from
dfillT the orbitals in both. These are also strong the surface energies of the solid and liquids using
bonds. the equation:
(3) Hydrogen bondshere a hydrogen atom, when
SAB c B  cA  cAB
covalently bonded to electronegative atoms
such as oxygen, fluorine or nitrogen, carries a where c A is the surface tension (energy) of the
slight positively charge and is therefore is liquid A, c A is the surface energy of the solid B
attracted to other electronegative atoms. The and c AB is the interfacial energy between the solid
hydrogen can therefore be thought of as being and liquid. S AB should be positive for the liquid to
shared, and the bond formed is generally weaker spread spontaneously over the solid.
than ionic or covalent bonds. The work of adhesion (WA) represents the energy
(4) Van-der-Waals bondsthese are some of the required to separate the two phases, and is given by:
weakest forms of interaction that arise from
WA cA c B  cAB :
dipoledipole and dipole-induced dipole attrac-
tions in polar molecules, and dispersion forces The greater the individual surface energies of the
with non-polar substances. solid and liquid relative to the interfacial energy, the
5) Hydrophobic bondsmore accurately described greater the work of adhesion.
as the hydrophobic effect, these are indirect The adsorption theory describes the attachment
bonds (such groups only appear to be attracted of adhesives on the basis of hydrogen bonding
to each other) that occur when non-polar groups and van der Waals forces. It has been proposed
are present in an aqueous solution. Water mole- that these forces are the main contributors to the
cules adjacent to non-polar groups form hydro- adhesive interaction. A subsection of this, the che-
gen bonded structures, which lowers the system misorption theory, assumes an interaction across
entropy. There is therefore an increase in the the interface occurs as a result of strong covalent
tendency of non-polar groups to associate with bonding.
each other to minimise this effect. The diffusion theory describes interdiffusion of
polymers chains across an adhesive interface. This
4.2. Theories of adhesion process is driven by concentration gradients and is
affected by the available molecular chain lengths and
There are six general theories of adhesion, which their mobilities. The depth of interpenetration depends
have been adapted for the investigation of mucoadhe- on the diffusion coefficient and the time of contact.
sion [11,14,15]. Sufficient depth of penetration creates a semi-perma-
The electronic theory suggests that electron trans- nent adhesive bond.
fer occurs upon contact of adhering surfaces due to The mechanical theory assumes that adhesion
differences in their electronic structure. This is pro- arises from an interlocking of a liquid adhesive (on
1560 J.D. Smart / Advanced Drug Delivery Reviews 57 (2005) 15561568

setting) into irregularities on a rough surface. How- mucoadhesive materials and a mucous membrane
ever, rough surfaces also provide an increased sur- (e.g. [1,17]) (Fig. 3).
face area available for interaction along with an
enhanced viscoelastic and plastic dissipation of Step 1 Contact stage: An intimate contact (wetting)
energy during joint failure, which are thought to be occurs between the mucoadhesive and mucous
more important in the adhesion process than a membrane.
mechanical effect [15]. Step 2 Consolidation stage: Various physicochemi-
The fracture theory differs a little from the other cal interactions occur to consolidate and
five in that it relates the adhesive strength to the forces strengthen the adhesive joint, leading to pro-
required for the detachment of the two involved sur- longed adhesion.
faces after adhesion. This assumes that the failure of
the adhesive bond occurs at the interface. However, 4.3.1. The contact stage
failure normally occurs at the weakest component, The mucoadhesive and the mucous membrane
which is typically a cohesive failure within one of have initially come together to form an intimate
the adhering surfaces. contact. In some cases these two surfaces can be
mechanically brought together, e.g. placing and
4.3. Mucoadhesion holding a delivery system within the oral cavity,
eye or vagina. In others the deposition of a particle
Due its relative complexity, it is likely that the is encouraged via the aerodynamics of the organ.
process of mucoadhesion cannot be described by For example within the nasal cavity or bronchi of
just one of these theories. In considering the mechan- the respiratory tract deposition onto the dstickyT
ism of mucoadhesion, a whole range dscenariosT for mucus coat is encouraged by processes such as
in-vivo mucoadhesive bond formation are possible inertial impaction, in order to dfilter outT particles
(Fig. 2). These include: from the airstream [18]. The gastrointestinal tract is
an example of an inaccessible mucosal surface
(1) Dry or partially hydrated dosage forms contact- where the adhesive material cannot be placed
ing surfaces with substantial mucus layers (typi- directly onto the target mucosal surface, or delivered
cally particulates administered into the nasal to the surface by organ design. In general, adhesion
cavity). and possible blockage of the gastrointestinal tract
(2) Fully hydrated dosage forms contacting surfaces would be potentially catastrophic. For larger parti-
with substantial mucus layers (typically particu- cles, peristalsis and other gastrointestinal movement
lates of many dFirst GenerationT mucoadhesives would help to force the dosage form into contact
that have hydrated in the luminal contents on with the mucosa. However little evidence of suc-
delivery to the lower gastrointestinal tract). cessful adhesion of larger dosage forms has yet
(3) Dry or partially hydrated dosage forms contact- been reported in the literature, other than the poten-
ing surfaces with thin/discontinuous mucus tially dangerous case of oesophageal adhesion [19].
layers (typically tablets or patches in the oral For smaller particles in suspension, adsorption onto
cavity or vagina). the gastrointestinal mucosa would be an essential
(4) Fully hydrated dosage forms contacting surfaces prerequisite for the adhesion process. Other exam-
with thin/discontinuous mucus layers (typically ples where an adsorption step would be required
aqueous semisolids or liquids administered into would be the administration of nanoparticle suspen-
the oesophagus or eye). sions to the precorneal region, or mouthwashes
containing microparticles.
It is unlikely that the mucoadhesive process will be The principles of the DLVO theory (described in
the same in each case. the 1940s by Derjaguin and Landau, and separately
In the study of adhesion generally, two steps in the by Verwey and Overbeek to explain the stability of
adhesive process have been identified [16], which colloids [18]) have been used to describe the phy-
have been adapted to describe the interaction between sicochemical processes involved in the adsorption of
 J.D. Smart / Advanced Drug Delivery Reviews 57 (2005) 15561568 1561

Hydrated
layer
Particle Particle

Mucus layer Mucus layer

a) Dry or partially hydrated dosage forms b) Fully hydrated dosage forms contacting
contacting surfaces with substantial mucus surfaces with substantial mucus layers (e.g.
layers (e.g. aerosolised particles deposited particle suspensions in the gastrointestinal
in the nasal cavity). tract).

Tablet Gel

c) Dry or partially hydrated dosage forms d) Fully hydrated dosage forms contacting
contacting surfaces with thin/ surfaces with thin/discontinuous mucus
discontinuous mucus layers (e.g. a tablet layers (e.g. aqueous microparticles
placed onto the oral mucosa). administered into the vagina).

Fig. 2. Some scenarios where mucoadhesion can occur.

bacteria onto surfaces [20,21]. The theory may from osmotic pressure effects as a result of the
therefore also be used in the consideration of the interpenetration of the electrical double layers, steric
adsorption process for small particles. Within the effects and also electrostatic interactions when the
body a particle will move due to Brownian motion, surface and particle carry the same charge. Attrac-
the flow of liquids within a body cavity and body tive forces arise form van der Waals interactions,
movements such as peristalsis. If a particle surface energy effects and electrostatic interactions if
approaches a surface it will experience both repul- the surface and particles carry opposite charges. The
sive and attractive forces. Repulsive forces arise relative strength of these opposing forces will vary
depending on the nature of the particle, the aqueous
Contact Consolidation environment, and the distance between the particle
stage stage and surface. For example, the smaller the particle,
the greater the surface-area-to-volume ratio and
Dosage Interaction therefore the greater the attractive forces. Particles
form area
can be weakly held at a secondary minimum (circa
Mucosa 10 nm separation), a region where the attractive
with
mucus forces are balanced by the repulsive forces allowing
the particles to be easily dislodged. For stronger
adsorption to occur, particles have to overcome a
Fig. 3. The two stages in mucoadhesion. repulsive barrier (the potential energy barrier) to get
1562 J.D. Smart / Advanced Drug Delivery Reviews 57 (2005) 15561568

closer to the surface (circa 1 nm). If this barrier is techniques to identify the type of bonds and groups
sufficiently small, or if the particle has sufficient involved although hydrogen bonds have been iden-
energy, then adsorption into the primary minimum tified as being important [1,31]. Polymer/mucosae
can occur. This type of adsorption would be interactions have been investigated by evaluating
required to allow a strong adhesive bond to form. surface energies [3234]. Although of interest,
This situation is made more complex by the fact these studies have met with varying degrees of
that the surface in question is usually a mucus gel success, which is unsurprising considering the het-
rather than a solid, and the particles in-vivo may erogeneous nature of mucosal surfaces and biopoly-
become hydrated and/or coated with biomolecules, mer solutions relative to the normally pure solvents
significantly altering their physicochemical properties and surfaces required in surface energy measure-
[2224]. The adhesive interaction necessary to retain ments. Polymers and biopolymers in solution tend
a dosage form may only need to be weak if the to rapidly accumulate at interfaces producing a sig-
forces promoting displacement are also small. A nificant reduction in the surface energy. It is also
consideration of many physicochemical models of noticeable when undertaking tensiometer studies
liquids at solid interfaces suggests that the liquid with these systems that the high affinity of materials
adjacent to the interface is stationary, with the rate like carbomers for water almost appears to have a
of flow increasing with distance from the surface dsuction-likeT effect, helping to hold to formulation
[25]. Many texts also refer to the presence of an onto a solid surface [30]. For surfaces with only
unstirred water layer at the surface of the gastroin- limited amounts of mucus, a dry mucoadhesive
testinal mucosae [26]. Mucous membranes typically polymer will almost certainly collapse the mucus
have a highly irregular topography on both the layer by extracting the water component of the
macroscopic and microscopic level so it is possible gel, allowing the polymer molecules the freedom
for small particulates to become lodged in these to interact by hydrogen bonding with the epithelial
surface folds and crevasses. Small particles may surface [17].
therefore be subjected only to minor dislodging However, when a substantial mucus layer is
stresses so only small adhesive interactions would present then the anti-adherent properties of mucus
be required to keep them in place. This might will need to be overcome if a strong adhesive joint
explain how apparently inert materials have been is to be formed. In this case the adhesive joint can
reported to be mucoadhesive (e.g. [2729]). be considered to contain three regions (Fig. 4), the
mucoadhesive, the mucosa and an interfacial region,
4.3.2. The consolidation stage consisting at least initially of mucus. To achieve
It has been proposed that if strong or prolonged strong adhesion, a change in the physical properties
adhesion is required, for example with larger for- of the mucus layer will be required otherwise it
mulations exposed to stresses such as blinking or will readily fail on application of a dislodging
mouth movements, then a second dconsolidationT stress.
stage is required. Mucoadhesive materials adhere There are essentially two theories as to how gel
most strongly to solid dry surfaces [30] as long as strengthening/consolidation occurs. One is based on
they are activated by the presence of moisture. a macromolecular interpenetration effect, which has
Moisture will effectively plasticize the system allow- been dealt with in a theoretical basis by Peppas and
ing mucoadhesive molecules to become free, con-
form to the shape of the surface, and bond
predominantly by weaker van der Waal and hydro-
Mucoadhesive dosage form
gen bonding. In the case of cationic materials such
Mucus layer
as chitosan, electrostatic interactions with the nega-
tively charged groups (such as carboxyl or sulphate) The mucosa
on the mucin or cell surfaces are also possible. The
mucoadhesive bond is by nature very heterogenous
making it extremely difficult to use spectroscopic Fig. 4. The three regions within a mucoadhesive joint.
 J.D. Smart / Advanced Drug Delivery Reviews 57 (2005) 15561568 1563

polymer (polycarbophil) showed penetration to a

depth of 60 Am after 4 h. However, the model
mucus used was a commercial mucin which is
thought to be degraded and therefore of limited
value as a model of native mucus [38,39]. The
porcine intestinal mucosa also used in this study
had been frozen prior to experimentation, a proce-
dure likely to result in significant damage to the
mucus gel layer. Further indirect evidence for inter-
penetration is based on the rheological effects of
mixing mucus with mucoadhesive gels [40,41].
Fig. 5. The interpenetration theory; three stages in the inteaction Rheological synergism, an increase in the resistance
between a mucoadhesive polymer and mucin glycoprotein. to elastic deformation (i.e. mucus gel strengthening)
is evident, and this would undoubtedly help conso-
lidate the adhesive joint.
Sahlin [15]. In this theory, based largely on the The second theory is the dehydration theory [17].
diffusion theory described by Voyutskii [35] for When a material capable of rapid gelation in an
compatible polymeric systems, the mucoadhesive aqueous environment is brought into contact with a
molecules interpenetrate and bond by secondary second gel water movement occurs between gels
interactions with mucus glycoproteins (Fig. 5). Evi- until equilibrium is achieved. A polyelectrolyte gel,
dence for this is provided by an ATIR FTIR study such as a poly(acrylic acid) will have a strong affinity
by Jabbari et al. [36]. In their study a thin cross- for water, therefore a high dosmotic pressureT and a
linked film of poly(acrylic acid) was formed on an large swelling force [42,43]. When brought into con-
ATR crystal. A mucin solution was placed into tact with a mucus gel it will rapidly dehydrate that
contact with this film and ATR-FTIR spectra col- gel and force intermixing and consolidation of the
lected over a period of time. Deconvolution of these mucus joint (Fig. 6) until equilibrium is reached. The
spectra revealed a peak after 6 min at 1550 cm 1 movement of water from mucus into a poly(acrylic
(which manifested itself as a small shoulder in the acid) film was observed by Jabbari et al. [36]. A
original spectrum) which was attributed to mucin mucus gel, on dehydration, goes from having lubri-
dimeric carboxylic CMO stretching and it was pro- cant to the opposite adhesive properties, as observed
posed that this indicated the presence of interpene- in studies by Mortazavi and Smart [44,45].
trating mucin molecules within the poly(acrylic The latter theory explains why mucoadhesion
acid) film. Another study [37] suggested that evi- arises very quickly, within a matter of seconds,
dence of substantial interpenetration was apparent while the former requires two large macromolecules
for poly(acrylic acid)s labeled with fluoresceina- to interpenetrate several Am within a short time.
mine. This was size dependent but even the largest The rheological synergy study suggests that as soon

Mucoadhesive dosage form

Hydrating region in dosage

form

Direction of water
movement
Dehydrated
Mucus layer
The mucosa

Fig. 6. The dehydration theory of mucoadhesion.

1564 J.D. Smart / Advanced Drug Delivery Reviews 57 (2005) 15561568

as mucus and mucoadhesive interpenetrate they are this. In all cases, eventually all formulations will be
likely to interact and form a surface gel layer that displaced by mucus or cell turnover [5355].
will substantially inhibit any further interpenetra-
tion. In an electron microscopy study by Lehr et
al. [46] no evidence of interpenetration could be 6. Some factors affecting mucoadhesion
seen in the micrometer range when fresh rat intest-
inal mucus was used. Clear evidence of rapid Several factors have been identified as affecting the
mucus gel dehydration has been observed using strength of the solid mucoadhesive joint [1,9,11].
light microscopy [44]. However, the dehydration Many studies have indicated an optimum molecular
theory is limited to explaining the adhesion arising weight for mucoadhesion, ranging from circa 104 Da
when a dry or partially hydrated formulation are to circa 4  106 Da, although accurately characterising
brought into contact with a substantial mucus gel, the molecular weight of large hydrophilic polymers is
and will not apply to the occasions where hydrated very difficult. Larger molecular weight polymers will
gels are involved. not hydrate readily to free the binding groups to
interact with a substrate, while lower molecular
weight polymers will form weak gels and readily
5. Removal mechanisms dissolve. The flexibility of polymer chains is believed
to be important for interpenetration and entanglement,
Adhesive failure will normally occur at the weakest allowing binding groups to come together. As the
component of the joint (Fig. 7). For weaker adhesives cross-linking of water-soluble polymers increases,
this would be the mucoadhesivemucus interface, for the mobility of the polymer chains decrease, although
stronger adhesives this would initially be the mucus this could also have a positive effect in restricting
layer, but later may be the hydrating mucoadhesive overhydration. Studies have shown that the mucoad-
material [47]. On application of a constant tensile hesive properties of polymers containing ionisable
stress to compacts of mucoadhesive polymers, joint groups are affected by the pH of the surrounding
failure was found by Mortazavi and Smart [48] to be a media [1]. For example, mucoadhesion of poly(acrylic
cohesive failure of the swelling polymer for all but the acid)s is favoured when the majority of the carbox-
weakest adhesives. The strength and durability of the ylate groups are in the unionised form, which occurs
adhesive joint will therefore depend on the cohesive at pHs below the pKa. However, in systems with a
nature of the weakest region. The mucoadhesive poly- high density of ionisable groups (e.g. carbomers or
mer in an aqueous environment can overhydrate to chitosans), the local pH within or at the surface of a
form a slippery mucilage, which is readily removed formulation will differ significantly from that of the
[7]. Controlling the rate and extent of hydration is surrounding environment [56].
required to produce prolonged adhesion, and strate- The strength of adhesion has been found to
gies such as cross-linking [4951] and introducing change with the initial dconsolidationT force applied
hydrophobic entities [52] has been tried to achieve to the joint, or the length of contact time prior to

Mucoadhesive dosage form

Fracture through the hydrated
gel layer
Fracture through the interface

Fracture through the

mucus gel layer

The epithelium

Fig. 7. The possible regions for mucoadhesive joint failure.

 J.D. Smart / Advanced Drug Delivery Reviews 57 (2005) 15561568 1565

testing. The presence of metal ions, which can inter- types of materials have been investigated that allow
act with charged polymers, may also affect the adhe- specificity, or prolong and strengthen the mucoadhe-
sion process. sion process. In some cases, existing mucoadhesive
polymers have been modified, while in others, new
materials are developed.
7. Liquid and semisolid adhesion One approach to produce improved mucoadhe-
sives has been to modify existing materials. For
7.1. Water soluble polymer adsorption example thiol groups (by coupling cysteine, thiogly-
colic acid, cysteamine) have been placed into a range
Mucoadhesive polymers (chitosan, polycarbophil of mucoadhesive polymers such as the carbomers,
and Carbopol 934) in dilute solutions were shown to chitosans and alginates by Bernkop-Schnurch et al.
bind to buccal cells in-vitro [57], and to bind and be [6467]. The concept is that in-situ they will form
retained in vivo for over 2 h [58]. The mechanism by disulphide links not only between the polymers them-
which this occurs is that of polymer adsorption at an selves thus inhibiting overhydration and formation of
interface, where polymers will naturally collect to the slippery mucilage, but also with the mucin layer/
reduce the surface energy and can then bind by the mucosa itself, thus strengthening the adhesive joint
formation of many weak bonds, mimicking the natural and leading to improved adhesive performance. This
role of mucins in saliva. The scenario is complicated interesting approach appears to be meeting with some
by the presence of mucins on the mucosae, which success.
means that polymers are adsorbing onto a hydrated The incorporation of ethyl hexyl acrylate into a
gel. In the case of cationic polymers like chitosan, the copolymer with acrylic acid in order to produce a
positive charge will favour binding to a negatively more hydrophobic and plasticized system was con-
charged surface although, in-vivo binding to soluble sidered by Shojaei et al. [68]. This would reduce
luminal mucins may inhibit this effect [59]. hydration rate while allowing optimum interaction
with the mucosal surface, and the mucoadhesive
7.2. Retention of liquids and gels force was found to be greater with the copolymer
than with poly(acrylic acid) alone.
More concentrated mucoadhesive dispersions have The grafting of polyethylene glycol (PEG) onto
been shown to be retained on mucosal surfaces for poly(acrylic acid) polymers and copolymers has also
extended periods [60,61]. The process by which been investigated [6971]. These copolymers were
polymeric dispersions spread and are retained on shown to have favourable adhesion relative to poly
mucosae will depend principally on the surface (acrylic acid) alone, in that the polyethylene glycol
energy of the solid and liquid (a positive spreading is proposed to promote interpenetration with the
coefficient), along with the rheology of the liquid. mucus gel [72]. Poly(acrylic acid)/PEG complexes
The dispersion will need to be sufficiently mobile to have also been developed as mucoadhesive materi-
allow spreading and interaction while not being so als [73].
mobile as to be readily dislodged. Systems that allow Poloxomer gels have been investigated as they are
in-situ gelation will clearly favour retention in this reported to show phase transitions from liquids to
case [62,63]. The interaction of the liquid or semi- mucoadhesive gels at body temperature and will
solid with biological fluids in terms of the rate and therefore allow in-situ gelation at the site of interest
extend of mixing and dissolution, will also be key [63]. Pluronics have also been chemically combined
factors influencing retention. with poly(acrylic acid)s to produce systems with
enhanced adhesion [74] and retention in the nasal
cavity [75].
8. New materials Dihydroxyphenylalanine (DOPA), an amino acid
found in mussel adhesive protein that is believed to
In order to overcome the limitations of first gen- lend to the adhesive process, has also been combined
eration doff-the-shelfT mucoadhesive materials, new with pluronics to enhance their adhesion [76].
1566 J.D. Smart / Advanced Drug Delivery Reviews 57 (2005) 15561568

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